Many drugs cannot be orally administered because the drug will either degrade or will not be orally bioavailable. For example, many drugs undergo acid catalyzed hydrolysis in the stomach, degradation in the gastrointestinal tract, or suffer from first-pass liver effect. Particularly, polypeptide and protein drugs are degraded in the gastrointestinal tract as the gastrointestinal tract protectively digests foreign peptides to deliver amino acid building blocks. There is, therefore, a need for formulations that allow oral administration of drugs that are subject to degradation in the gastrointestinal tract, first-pass liver effect and/or lack permeability in the gastrointestinal tract.
The oral mucosa has been identified as an ideal target to systemically deliver drugs. Permeation through the oral mucosa avoids gastrointestinal degradation and first-pass hepatic effect. Further, permeation through the oral mucosa preempts problems associated with poor gastrointestinal permeation. Thus, a formulation that transports a therapeutically effective agents across the oral mucosa is needed.
Transmucosal permeation occurs through two main pathways—intracellular and intercellular. Intracellular permeation occurs when substances are transferred across the epithelial cell membrane and into the cell prior to systemic delivery. Passive or active transport can drive intracellular permeation. Intercellular permeation occurs when substances diffuse through intercellular lipids. There are two routes associated with the intercellular pathway. The hydrophilic route travels the narrow aqueous regions adjacent to the polar head groups of the membrane lipids. The hydrophobic route travels through the epithelial cell's lipid bilayer.
Diabetes, also referred to as diabetes mellitus, is a metabolic disease that causes high blood glucose level. When blood glucose level rises in a healthy patient, the pancreas converts proinsulin, which is a prohormone precursor to insulin, to another protein called C-peptide and insulin. Insulin promotes the absorption of glucose from the blood. The high blood glucose level is due to either failure to produce enough insulin or to the development of insulin resistance. Failure to produce enough insulin results in diabetes Type I (juvenile diabetes). Type 2 diabetes results from insulin resistance. A third type of diabetes is gestational diabetes which occurs when a pregnant women, without a previous history of diabetes, develops a high blood glucose level. Side effects of this high blood sugar level include frequent urination, increased thirst and increased hunger. If not treated, the high glucose level may cause more serious complications, e.g. hyperglycemia, diabetic ketoacidosis, nonketotic hyperosmolar coma, heart disease, stroke, kidney disease, and nerve damage. Type 1 diabetes is typically treated with insulin or synthetic insulin analogs. Type 2 diabetes may require insulin if other medications fail. With exception to a recently approved pulmonary release formulation, patients requiring insulin must parenterally administer insulin.
Non-parenteral dosage forms for biologically active peptides, especially insulin, are of big demand. Among different non-injectable delivery methods of insulin, oral administration of this peptide is one of the most promising delivery methods. The pharmaceutical industry has searched for an oral insulin for more than 90 years. Indeed, the first oral insulin experiments in man occurred in 1922. Since then, numerous patents and publications have advertised an oral method of insulin administration and numerous formulations have entered clinical trials. Despite tremendous efforts, very few products are marketed or have reached late stages of development. Due to peptide nature, insulin molecule in oral formulations must be protected from enzymatic degradation in the gastro-intestinal tract. It requires incorporation of protease inhibitors into formulations, and extended use of such inhibitors may cause serious side effects.
Inhalable insulin formulation (e.g., Exubera®) was withdrawn from the market due to insufficient uptake in the market. Oral sprays (e.g., Ora-Lyn™) require multiple administrations and an expensive and complex delivery device. Intranasal peptide delivery has limitations due to often irritation and sensitization. (Heinemann et al., “Oral Insulin and Buccal Insulin: A Critical Reappraisal,” J. Diabetes Sci. Technol., 2009, 3(3): 568-584; Soares, S., “Novel Non-Invasive Methods of Insulin Delivery,” Expert Opin. Drug Deliv., 2012, 9(12): 1539-1558).
Intraoral route of delivery of different peptides attracted tremendous attention in the last decades. Oral mucosa has good potential as an excellent place for enhanced delivery of various drugs, including peptides.
Buccal and sublingual mucosa is relatively easy penetrable for small, especially hydrophobic, molecules (below 500 Dalton). In order to overcome penetration resistance of mucosa to large hydrophilic peptide molecules, various approaches have been exploited. These approaches include the use of penetration enhancers such as polar solvents—liquid PEGs, Propylene glycol, DMSO, N-Mehtylpyrrolidone; lipid disturbants—Azone®, Decylmethylsulfoxide; non-ionic surfactants—polysorbates, poloxamers, alkyl glucosides and other sugar esters; anionic surfactants—sodium lauryl sulfate (SLS), salts of fatty acid; phospholipids—lecithin, phosphatidylcholines, other phospholipids; bile acids—sodium cholate, desoxycholate, taurocholate and analogs; high concentrations of terpenes—menthol, borneol, eucalyptol; chelators—EDTA, citric acid, etc.; lipids and esters—mono-, di- and triglycerides, glycol esters, various cyclodextrines and other compounds. (Kinesh et al., “Novel Approaches for Oral Delivery of Insulin and Current Status of Oral Insulin Products,” International Journal of Pharmaceutical Sciences and Nanotechnology, 2010, 3(3): 1057-1064). Furthermore, WO 2012/104834 teaches a buccal bioadhesive polymeric film loaded with insulin and penetration enhancers; WO 2011/086093 describes liquid self-nanoemulsifying systems for oral delivery of acylated derivatives of insulin based on combination of polar solvent and non-ionic surfactants, and WO 2005/089722 describes the sublingual composition of insulin combined with chelators such as EDTA and citric acid in order to prevent insulin's aggregation into hexamers.
The influence of various penetration enhancers on the membrane fluidity and insulin delivery “in vitro” and “in vivo” was investigated by Cui et al. (Cui et al., “Sublingual delivery of insulin: effects of enhancers on the mucosal lipid fluidity and protein conformation, transport, and in vivo hypoglycemic activity,” Biol. Pharm. Bull., 2005, 28(12): 2279-2288). The enhancing effects may be due to one or multiple factors such as increasing the mucosal lipid fluidity, directly loosing the tight junction of epithelia, and other parameters. Cui et al. evaluated effects of enhancers on the mucosal lipid fluidity and protein conformation, transport, and hypoglycemic activity in normal rats. The formulations contained high levels of the enhancers—5 to 10% of the liquid composition. For evaluating transport of insulin, human immortalized oral epithelial cell monolayer was used. The penetration enhancers that were used include hydroxylpropyl-beta-cyclodextrin (HP-beta-CD), chitosan, polyethylene-polypropylene glycol, polyoxyethylene lauryl ether, polysorbate 80, egg lecithin and oleic acid.
Aungst et al. tested efficacy of various penetration adjuvants, including non-ionic surfactants, bile salts, fatty acids, enzymes, polar solvents and their combinations on buccal insulin delivery in high concentration. (Aungst et al., “Comparison of the effects of various transmucosal absorption promoters on buccal insulin delivery,” International Journal of Pharmaceutics, 1989, 53: 227-235). It was found that most of such adjuvants are effective only when used at high concentrations (5-10%).
In order to improve bioavailability of transmucosally delivered peptides, the peptides can be incorporated into nanoparticles, micro- and nanoemulsions, micellar solutions or self-emulsifying compositions. Various solid, semi-solid and liquid dosage forms as well as pressurized sprays, buccal films and patches were proposed for intraoral administering of peptides. (Xu et al., “Hypoglycaemic Effect of a Novel Insulin Buccal Formulation nn Rabbits,” Pharmacological Research, 2002, 46(5):459-467; Elsayed et al., “Formulation and Characterization of an Oily-Based System for Oral Delivery of Insulin,” Eur. J. Pharm. Biopharm., 2009, 73: 269-279; Sarmento et al., “Oral Insulin Delivery by Means of Solid Lipid Nanoparticles,” Inter. J. Nanomed., 2007, 2(4): 743-749).
For example, U.S. Pat. No. 6,290,987 discloses a mixed liposomal formulation containing alkylsulfate salts delivered intra-orally as a spray. U.S. Pat. No. 6,350,458 denotes use of mixed micelles for transbuccal delivery of insulin. Proposed oral spray compositions contain high concentration of alkylsulfates, such as sodium lauryl sulfate, possessing high irritation potential for oral mucosa.
Furthermore, U.S. Pat. No. 6,635,617 teaches pulmonary delivery of insulin in combination with menthol, using bronchodilatory properties of this terpene. U.S. Pat. No. 7,112,561 describes use of macrocyclic penetration enhancers in nasal formulations for insulin emulsions in acidic conditions. Moreover, U.S. Pat. No. 4,579,730 describes cholate complexes of insulin with protease inhibitors for oral delivery.
The use of various complexes and biodegradable nanoparticles with sodium deoxycholate as ion-pair reagent for enhancement of insulin delivery has also been described. (Sun et al., “Hydrophobic Ion Pairing of an Insulin—Sodium Deoxycholate Complex for Oral Delivery of Insulin,” Int. J. Nanomed., 2011, 6:3049-3056).
Various penetration enhancers were proposed for increasing of transmucosal transportation of peptides and proteins: polar solvents (PG, DMSO); terpenes (menthol, borneol); surfactants (Brij, SLS). For example, U.S. Patent Publication No. 2004/0258623 describes oral spray containing insulin, lecithin, polar solvent and borneol as penetration enhancers. U.S. Patent Publication No. 2009/0274758 describes solid composition for intraoral delivery of different types of biologically active molecules, including insulin, using hydrophilic polymeric matrixes or liquid formulations, containing liposomes or pro-liposomal combinations together with menthol as a penetration enhancer and sodium lauryl sulfate (SLS) and other anionic surfactants. Due to proposed very high concentrations of SLS and menthol, such formulations should possess serious local irritation potential. Shojaei et al. teach an effective transbuccal penetration enhancer. (Shojaei et al., “Transbuccal Permeation of a Nucleoside Analog, Dideoxycytidine: Effects of Menthol as a Permeation Enhancer,” Int. J. Pharm., 1999, 192: 139-146).
Significant improvement of transdermal or transmucosal penetration for polar compounds can be achieved by applying high concentrations of such enhancers. In most cases it associated with serious local irritation, especially for intranasal route of administration. Tissue damage and delipidization, loss of taste and odor sense may be caused by administration of formulations with high concentration of penetration enhancers.
Various microemulsions and nanoemulsions, especially in self-emulsifying pre-concentrates, were widely investigated as delivery systems for oral delivery of peptides, including insulin. Spontaneously formed colloidal dispersions are absorbed in gastro-intestinal tract and could increase efficacy of drug absorption in some cases. As described in WO 2011/086093, combination of insulin and polar organic solvent with low content of lipids and elevated concentration of surfactants with high HLB, administered into duodenum or distant parts of intestine, improved insulin delivery via gastro-intestinal tract.
Transmucosal delivery improvement can be achieved with various eutectic mixtures. An eutectic mixture is a mixture of two or more substances that melts at a temperature lower than the melting point of any single component or any other mixture of them. A simple eutectic mixture consists of two compounds that are completely miscible in liquid state but only to a very limited extent in a solid state. (Remington: The Science And Practice of Pharmacy, 2000, 20th edition, Lippincott Williams & Wilkins, Philadelphia, pp. 177). Formation of eutectic mixtures can not be predicted based on molecular structure and composition of components. The properties of such mixtures can be determined only experimentally.
The well known eutectic mixtures used in pharmaceutical development are menthol and camphor mixtures having high solubilizing properties for non-steroidal anti-inflammatory compounds (U.S. Pat. No. 7,138,394). Phenol or menthol combinations with various compounds, cause incompatibility problems in pharmaceutical formulations; e.g., in mixtures with antipyrine, salycilates, acetaminophen and alkaloids. (Remington: The Science And Practice of Pharmacy, 2000, 20th edition, Lippincott Williams & Wilkins, Philadelphia, pp. 1045).
The eutectic mixture of solid crystalline bases of Lidocaine and Prilocaine is liquid at room temperature and had been successively used for preparation of topical local anesthetic cream with enhanced efficacy. (EMLA® Product Information, available at: www.medicines.org.au/files/appemlac.pdf).
Menthol was found to form eutectic mixtures with testosterone, cholesteryl oleate, and ceramides. Eutectic mixture of menthol (m.p. ˜42° C.) and testosterone (m.p. ˜155° C.) is solid at body temperature (melting point ˜40° C.) but shows increased transdermal penetration of the drug. The decrease in melting temperature resulted in an increase in the solubility of testosterone in an aqueous ethanol vehicle by 2.8-fold, which caused a corresponding 2.8-fold increase in the flux of testosterone. A further increase in skin flux, to eight times the base line, could be attributed to the effect of high concentration of menthol on the skin barrier properties. (Kaplun-Frischoff, et al., “Testosterone Skin Permeation Enhancement by Menthol Through Formation of Eutectic with Drug and Interaction with Skin Lipids,” J. Pharm. Sci., 1997, 86(12):1394-1399).
U.S. Patent Publication No. 2007/024261 describes several liquid eutectic compositions, suitable for oral administration of encapsulated drug formulation dosage. U.S. Pat. No. 8,790,723 describes methods of solid dosage forms preparation of coenzyme Q10 with enhanced bioavailability.
Goldberg found that eutectic mixtures may provide a unique approach for increasing dissolution rates. (Goldberg et al., “Increasing Dissolution Rates and Gastrointestinal Absorption of Drugs Via Solid Solutions and Eutectic Mixtures I. Theoretical Considerations and Discussion of the Literature,” J. Pharm. Sci., 1965, 54(8):1145-1148; Goldberg et al., “Increasing Dissolution Rates and Gastrointestinal Absorption of Drugs Via Solid Solutions and Eutectic Mixtures II: Experimental Evaluation of a Eutectic Mixture: Urea-Acetaminophen System,” J. Pharm. Sci., 1966, 55(5):482-487). Eutectic mixtures of fatty acids, liquid at body temperatures, are described by Zhang et al. (Zhang et al., “Thermal studies on the solid-liquid phase transition in binary systems of fatty acids,” Thermochimica Acta., 2001, 369: 157-160).
Bile acids and salts thereof are widely used as penetration enhancers for peptides and proteins. Das et al. developed optimized buccal insulin-loaded Pluronic F-127 gels. Bioadhesive gels with insulin, surfactants and bile acid derivatives for buccal and sublingual delivery were prepared. [N. Das et al., “Development and in Vitro Evaluation of Insulin-Loaded Buccal Pluronic F-127 Gels,” Pharmaceutical Development and Technology, 2010, 15(2):192-208). Bioadhesive sublingual tablets containing chitosan and various biologically active compounds, including insulin and sildenafil were described in WO 2010/118516.
Nevertheless, despite numerous attempts, the need to develop a non-invasive delivery system for insulin is still unmet and compels development of stable convenient intra-oral dosage forms of insulin. Accordingly, there is a need for a therapeutically effective oral insulin formulation. The present teachings provides formulations that permeate drugs through the oral mucosa.